Cancer-Associated Fibroblasts Induce a Collagen Cross-link Switch in Tumor Stroma

摘要: Intratumoral collagen cross-links heighten stromal stiffness and stimulate tumor cell invasion, but it is unclear how cross-linking regulated in epithelial tumors. To address this question, we used KrasLA1 mice, which develop lung adenocarcinomas from somatic activation of a KrasG12D allele. The tumors mice were highly fibrotic contained cancer-associated fibroblasts (CAF) that produced generated gels. In xenograft by injection wild-type with adenocarcinoma cells alone or combination CAFs, the total concentration was same without coinjected had higher hydroxylysine aldehyde–derived (HLCC) lower lysine-aldehyde–derived (LCCs). Therefore, postulated an LCC-to-HLCC switch induced CAFs promotes migratory invasive properties cells. test hypothesis, created coculture models are positioned interstitially peripherally aggregates, mimicking distinct spatial orientations human cancer. both contexts, enhanced three-dimensional (3D) Tumor aggregates attached to CAF networks on Matrigel surface dissociated migrated networks. Lysyl hydroxylase 2 (PLOD2/LH2), drives HLCC formation, expressed LH2 depletion abrogated ability promote invasion migration. Implications: induce cross-link stroma influence Mol Cancer Res; 14(3); 287–95. ©2015 AACR . This article featured Highlights This Issue, [p. 239][1] [1]: /lookup/volpage/14/239?iss=3